According to the American Cancer Society, approximately 25,000 people will die from leukemia this year. Despite numerous treatment advances, patients with acute lymphoblastic leukemia (ALL) continue to be high-risk and have a poor prognostic outlook. While some novel therapeutic modalities are being implemented, drug resistance, cancer relapse, and off-target toxicity indicate a considerable clinical need still exists meaning safer, more efficient treatment systems must be developed. This collaborative work brings together expertise from the fields of chemical engineering, materials science, molecular biology, immunology, and clinical medicine to provide a unique approach to this difficult problem. Preliminary data provides considerable evidence that inhibition of the Plenty of SH3 Domains (POSH) scaffold complex leads to a blockade in proliferation and/or an induction in significant apoptosis in the vast majority (15 of 16) of T cell and B cell leukemias evaluated to date. While promising, the POSH inhibitor peptide therapeutic (POSHINHIB) is not readily internalized and does not specifically target lymphocytes, both of which greatly limit its bioactivity. We hypothesize that by combining cell- targeting aptamers (Apts), cell penetrating peptides (CPPs), and peptide amphiphile micelles (PAMs), a novel biomaterial can be created capable of treating T cell and B cell leukemia. This hypothesis will be tested in Specific Aim 1 by the synthesis and characterization of Apt-conjugated and CPP-modified POSHINHIB amphiphile micelles (Apt~A/Tat-POSHINHIBAMs). In Specific Aim 2, Apt~A/Tat-POSHINHIBAM function and specificity for the in vitro treatment of T cell and B cell ALL that do not respond well to conventional cancer therapeutics will be assessed. Specific Aim 3 will consist of preliminary experiments designed to evaluate the in vivo antineoplastic effects of Apt~A/Tat-POSHINHIBAM against human leukemia in a murine xenograft model. This work is expected to provide a deeper understanding into how directed delivery and biomaterials structure influence the biological efficacy of therapeutic peptides. While high risk, preliminary data support the substantial therapeutic potential of Tat- POSHINHIB, show our capacity to fabricate POSHINHIBAMs, and demonstrate Apt~A/PAMs possess enhanced selective targeting. The proposed research plan will build on these initial results to create a complex delivery device capable of becoming a clinically applicable treatment. In addition, the modular nature of the nanoparticle therapeutics developed in this research all them to serve as a platform technology that can be leveraged for the treatment of other cancers as well as autoimmune diseases.